Ectopic pituitary adenoma associated with an empty sella presenting with hearing loss: case report with literature review.

Ectopic pituitary adenomas are uncommon entities that may pose substantial diagnostic challenges. In the majority of these cases, patients present with endocrine and/or nasal obstruction symptoms. We report the case of an ectopic pituitary adenoma in a 76-year-old man with an empty sella who initially presented with right-sided hearing loss progressing to bilateral hearing loss over the next 4 years. Neuroimaging studies revealed a large, expansile central skull base mass replacing the clivus and sphenoid sinus, and invading the internal auditory canals and inner ear bilaterally. The tumor also involved the floor of the middle cranial fossae and bilateral medial temporal and occipital bones. Histopathologic examination, including immunohistochemical studies, revealed a sparsely granulated lactotroph adenoma. Hearing loss in a patient with ectopic pituitary adenoma constitutes an extremely unusual presentation. This case was further complicated by the presence of an empty sella and the absence of symptoms related to hyperprolactinemia.

Cystic Glioblastoma: A Mimicker of Infection? A Case Report and Literature Review.

Glioblastoma multiforme (GBM) is the most frequent malignant and aggressive type of glioma. Most cases of GBM present as a single solitary solid tumor; however, there are rare instances in which it may present as a cystic lesion. Here, we report an even rarer case of GBM presenting as bilateral multicystic lesions, mimicking infectious etiology. Our case highlights the importance of identifying clinical features of cystic GBM to ensure early diagnosis and treatment. A literature review was conducted in PubMed, looking at the common characteristics and treatment options for cystic GBM.

PKMζ is necessary and sufficient for synaptic clustering of PSD-95.

The persistent activity of protein kinase Mzeta (PKMζ), a brain-specific, constitutively active protein kinase C isoform, maintains synaptic long-term potentiation (LTP). Structural remodeling of the postsynaptic density is believed to contribute to the expression of LTP. We therefore examined the role of PKMζ in reconfiguring PSD-95, the major postsynaptic scaffolding protein at excitatory synapses. In primary cultures of hippocampal neurons, PKMζ activity was critical for increasing the size of PSD-95 clusters during chemical LTP (cLTP). Increasing PKMζ activity by overexpressing the kinase in hippocampal neurons was sufficient to increase PSD-95 cluster size, spine size, and postsynaptic AMPAR subunit GluA2. Overexpression of an inactive mutant of PKMζ did not increase PSD-95 clustering, and applications of the ζ-pseudosubstrate inhibitor ZIP reversed the PKMζ-mediated increases in PSD-95 clustering, indicating that the activity of PKMζ is necessary to induce and maintain the increased size of PSD-95 clusters. Thus the persistent activity of PKMζ is both necessary and sufficient for maintaining increases of PSD-95 clusters, providing a unified mechanism for long-term functional and structural modifications of synapses.

Postsynaptic degeneration as revealed by PSD-95 reduction occurs after advanced Aß and tau pathology in transgenic mouse models of Alzheimer's disease.

Impairment of synaptic plasticity underlies memory dysfunction in Alzheimer's disease (AD). Molecules involved in this plasticity such as PSD-95, a major postsynaptic scaffold protein at excitatory synapses, may play an important role in AD pathogenesis. We examined the distribution of PSD-95 in transgenic mice of amyloidopathy (5XFAD) and tauopathy (JNPL3) as well as in AD brains using double-labeling immunofluorescence and confocal microscopy. In wild type control mice, PSD-95 primarily labeled neuropil with distinct distribution in hippocampal apical dendrites. In 3-month-old 5XFAD mice, PSD-95 distribution was similar to that of wild type mice despite significant Aß deposition. However, in 6-month-old 5XFAD mice, PSD-95 immunoreactivity in apical dendrites markedly decreased and prominent immunoreactivity was noted in neuronal soma in CA1 neurons. Similarly, PSD-95 immunoreactivity disappeared from apical dendrites and accumulated in neuronal soma in 14-month-old, but not in 3-month-old, JNPL3 mice. In AD brains, PSD-95 accumulated in Hirano bodies in hippocampal neurons. Our findings support the notion that either Aß or tau can induce reduction of PSD-95 in excitatory synapses in hippocampus. Furthermore, this PSD-95 reduction is not an early event but occurs as the pathologies advance. Thus, the time-dependent PSD-95 reduction from synapses and accumulation in neuronal soma in transgenic mice and Hirano bodies in AD may mark postsynaptic degeneration that underlies long-term functional deficits.

Atypical protein kinase C in neurodegenerative disease I: PKMzeta aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease.

Protein kinase Mzeta (PKMzeta), an atypical protein kinase C (PKC) isoform, plays a key role in the maintenance of long-term potentiation (LTP), a persistent enhancement of AMPA receptor-mediated synaptic transmission, as well as in the persistence of memory in Drosophila. Because memory impairment in Alzheimer disease (AD) has been attributed to disruption of synaptic plasticity, we investigated the expression and distribution of PKMzeta in this disorder. We found that PKMzeta accumulated in neurofibrillary tangles (NFTs), whereas conventional and novel PKC isoforms did not. Unlike tau, which is present in all NFTs regardless of location, PKMzeta was found in a subset of NFTs restricted to limbic or medial temporal lobe structures (i.e. hippocampal formation, entorhinal cortex, and amygdala), areas implicated in memory loss in AD. Interestingly, PKMzeta was not identified in any NFTs in control brains derived from 6 elderly individuals without known cognitive impairment. In medial temporal lobe structures in AD, PKMzeta also occurred within abnormal neurites expressing MAP2, GluR1 and GluR2 as well as in perisomatic granules expressing GluR1 and GluR2, suggesting that aggregation of PKMzeta disrupts glutamatergic synaptic transmission. Together, these findings suggest a link between PKMzeta-mediated synaptic plasticity and memory impairment in AD.

Atypical protein kinase C in neurodegenerative disease II: PKCiota/lambda in tauopathies and alpha-synucleinopathies.

To study the role of atypical protein kinase C (aPKC) in neurodegenerative disease, we investigated the distribution of PKCiota/lambda, an aPKC isoform, in a variety of tauopathies and alpha-synucleinopathies. Immunohistochemical study revealed PKCiota/lambda within tau-positive neurofibrillary inclusions in Alzheimer disease (AD), progressive supranuclear palsy, corticobasal degeneration (CBD), and Pick disease (PiD), within alpha-synuclein-positive Lewy bodies in idiopathic Parkinson disease and dementia with Lewy bodies, as well as within glial inclusions in multisystem atrophy. We also observed PKCiota/lambda label of actin-rich Hirano bodies in AD, PiD, and elderly individuals. Double immunolabeling and fluorescence resonance energy transfer demonstrated close physical association between PKCiota/lambda and phospho-tau or alpha-synuclein in some neurofibrillary tangles and Lewy bodies. Furthermore, PKCiota/lambda colocalized with p62, a chaperone protein that binds to both aPKC and ubiquitin, in most of these inclusions. PKCiota/lambda also closely associated with the inactivated form of glycogen synthase kinase-3beta, GSK-3beta[ser9]. Together, these findings suggest that PKCiota/lambda may play a role in common mechanisms involving the pathogenesis of neurodegenerative disease.

A Rare Case of Renal Cell Carcinoma With Leiomyomatous Stroma and Concomitant Ruptured Adrenal Aneurysm.

Here we report a rare case of coexisting renal cell carcinoma (RCC) with leiomyomatous stroma and a ruptured adrenal aneurysm. The patient was a 75-year-old woman with acute abdominal pain. Imaging studies showed a left peri-renal hematoma and a mass in the left kidney. Left nephrectomy and adrenalectomy were performed. Pathological examination showed a ruptured aneurysm in the left adrenal gland. The renal mass was composed of tubules and acini of epithelial cells and a prominent leiomyomatous stroma. The tumor cells were positive for carbonic anhydrase IX, cytokeratin 7, and negative for AMACR, consistent with clear cell (tubulo) papillary RCC.

Distinct breast cancer subtypes in women with early-onset disease across races.

BACKGROUND: Racial disparities among breast cancer (BCa) patients are known but not well studied in early-onset BCa. We analyzed molecular subtypes in early-onset BCa across five major races. METHODS: A total of 2120 cases were included from non-Hispanic White (NHW), African American (AA) and Hispanic, Chinese and Indian. Based on ER, PR and HER-2 status, BCa was classified into 4 intrinsic subtypes as Luminal A, Luminal B, HER2/neu overexpression and Triple negative BCa (TNBC) subtypes. Data was stratified according to race and age as younger/early-onset group (40-years and younger) and older group (50-years and older). RESULTS: In early-onset BCa, incidence of TNBC was significantly higher (p = 0.0369) in Indian women followed by AA, Hispanic, NHW and Chinese women. Incidence of Her2 over-expression subtype also was highest in Indian women, followed by Hispanic, Chinese, AA and NHW women. In contrast, Luminal B subtype was most significantly higher in AA women (p = 0.0000) followed by NHW (p = 0.0002), Chinese (p = 0.0003), Hispanic (0.0128) and Indian (p = 0.0468) women. Luminal A subtype was most significantly reduced in Indian women (p = 0.0113) followed by Hispanic, AA, NHW and Chinese women. These results were based on statistical analysis with the mean of older group populations. CONCLUSIONS: These results show significant disparities in receptor subtypes across races. This study will contribute in developing optimal clinical trial protocols and personalized management strategies for early-onset BCa patients.

Matching biochemical and functional efficacies confirm ZIP as a potent competitive inhibitor of PKMζ in neurons.

PKMζ is an autonomously active, atypical protein kinase C (aPKC) isoform that is both necessary and sufficient for maintaining long-term potentiation (LTP) and long-term memory. The myristoylated ζ-pseudosubstrate peptide, ZIP, potently inhibits PKMζ biochemically in vitro, within cultured cells, and within neurons in hippocampal slices, and reverses LTP maintenance and erases long-term memory storage. A recent study (Wu-Zhang et al., 2012), however, suggested ZIP was not effective on a PKMζ fusion protein overexpressed in cultured cells. Chelerythrine, a redox-sensitive PKC inhibitor that inhibits PKMζ and disrupts LTP maintenance and memory storage, was also reported by Wu-Zhang et al. (2012) not to inhibit the expressed PKMζ fusion protein. However, the efficacy of inhibitors on endogenous enzymes in cells may not be adequately assessed in expression systems in which levels of expression of exogenous enzymes greatly exceed those of endogenous enzymes. Thus, we show, biochemically, that when PKMζ reaches a level beyond that necessary for substrate phosphorylation such that much of the enzyme is excess or 'spare' kinase, ZIP and chelerythrine do not effectively block substrate phosphorylation. We also show that the cellular overexpression techniques used by Wu-Zhang et al. (2012) increase kinase levels ~30-40 fold above normal levels in transfected cells. Using a mathematical model we show that at such level of overexpression, standard concentrations of inhibitor should have no noticeable effect. Furthermore, we demonstrate the standard concentrations of ZIP, but not scrambled ZIP, inhibit the ability of PKMζ to potentiate AMPAR responses at postsynaptic sites, the physiological function of the kinase. Wu-Zhang et al. (2012) had also claimed that staurosporine, a general kinase inhibitor that does not effectively inhibit PKMζ biochemically in vitro, nonetheless indirectly blocked the PKMζ fusion protein overexpressed in cultured cells by inhibiting phosphoinositide-dependent protein kinase-1 (PDK1). However, here we show that staurosporine does not affect PDK1 phosphorylation of the endogenous PKMζ in hippocampal slices. Thus, the biochemical in vitro effects of PKMζ inhibitors correspond with their intracellular effects, and ZIP and chelerythrine, together with scrambled ZIP and staurosporine as controls, are effective tools to examine the function of PKMζ in neurons. This article is part of a Special Issue entitled 'Cognitive Enhancers'.